For over a decade, our research program has focused on the psychoneuroimmunology of interleukin (IL)-2, with particular emphasis on its effects on exploratory motor activity and stereotypic behavior. IL-2, a cytokine that potently modulates dopaminergic activity in the mesolimbic and mesostriatal systems, is implicated in the etiology and pathogenesis of psychiatric abnormalities, notably psychosis, schizophrenic- like behavior, and cognitive deficits. A common dimension of these abnormalities is the expression of repetitive motor stereotypies. In this application, we propose to more closely examine the effects of IL-2 on repetitive stereotypic behavior and to identify neural and pharmacological substrates of these effects. To that end, we developed a mouse model that has produced a novel and robust effect: whereas single intraperitoneal (ip) or subcutaneous (sc) injections of IL-2 induce modest behavior-activating effects, with repeated injections mice display marked increases in repetitive motor stereotypies, notably rearing and sniffing behavior with head swaying and climbing behavior. Levels of stereotypic behavior are significantly elevated within 2-3 days of initiation of IL-2 treatment, and are most pronounced in mice tested in a novel environment. In parallel with these behavioral changes, IL-2 induces marked increases in Fos-like immunoreactivity in the rostral striatum, suggesting that IL-2 induces coordinate changes in levels of stereotypic behavior and striatal activation patterns. Based on these findings, we propose to systematically and rigorously characterize a new direction - the psychoneuroimmunology of cytokine (IL-2)-induced stimulation of stereotypic behavior. The overarching hypothesis is that repeated peripheral injections of IL-2 induce an increased expression of repetitive motor stereotypies that reflect coordinate changes in striatal activation patterns and that are mediated principally through dopaminergic receptors.